This is an integrative program of Huntington's disease research ranging from the molecular to the clinical. One project involves a longitudinal clinical study of patients with HD and related phenotypes from a set of well characterized families deriving from an epidemiologic sample. A second project uses structural and functional imaging for longitudinal measurement of cerebral atrophy and dysfunction with a special interest in early HD and pre-symptomatic gene positive individuals. A third project involves biochemical and cell biologic studies of the pathogenesis of HD, focusing on the potential proteolytic cleavage of huntingtin, the possible involvement of huntingtin associated proteins, and the use of cell models to understand pathways of cell death and develop therapeutic interventions. A fourth project will use pharmacologic and genetic manipulations of our HD transgenic mouse model to determine possible means of ameliorating the phenotype. These projects are supported by four cores. One core provides administrative and statistical support. A second core provides examination, diagnosis and longitudinal follow up of patients. A third core provides neuropathologic examination, diagnosis, and tissue for research. A forth core provides genetic testing and identification of genetic variants which contribute to phenotypes. Overall, the goal of the program is to better understand the molecular and cellular pathogenesis of HD, and develop and test new therapeutic approaches.